EP1032560B1 - An 4-stellung substituierte 2-pyrrolidinon-derivate zur verringerung des extrazellulären glutamat-spiegels - Google Patents

An 4-stellung substituierte 2-pyrrolidinon-derivate zur verringerung des extrazellulären glutamat-spiegels Download PDF

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Publication number
EP1032560B1
EP1032560B1 EP98963476A EP98963476A EP1032560B1 EP 1032560 B1 EP1032560 B1 EP 1032560B1 EP 98963476 A EP98963476 A EP 98963476A EP 98963476 A EP98963476 A EP 98963476A EP 1032560 B1 EP1032560 B1 EP 1032560B1
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EP
European Patent Office
Prior art keywords
radicals
pyrrolidinone
alkyl
alkylamino
alkoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
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EP98963476A
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German (de)
English (en)
French (fr)
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EP1032560A1 (de
Inventor
Thomas J. Feuerstein
Rainer KNÖRLE
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Albert Ludwigs Universitaet Freiburg
Universitaetsklinikum Freiburg
Original Assignee
Albert Ludwigs Universitaet Freiburg
Universitaetsklinikum Freiburg
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Priority to EP04022320A priority Critical patent/EP1486487A1/de
Priority to DK98963476T priority patent/DK1032560T3/da
Publication of EP1032560A1 publication Critical patent/EP1032560A1/de
Application granted granted Critical
Publication of EP1032560B1 publication Critical patent/EP1032560B1/de
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/267—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/54—Spiro-condensed

Definitions

  • Glutamate (Glu) is the main excitatory transmitter in the central nervous system.
  • High extracellular concentrations of glu in the extracellular space lead to excitotoxic damage (Siesjö BK, Bengtsson F, Grampp W, Theander S, 1989, Calcium, excitotoxins, and neuronal death in the brain.
  • excitotoxic damage (Siesjö BK, Bengtsson F, Grampp W, Theander S, 1989, Calcium, excitotoxins, and neuronal death in the brain.
  • Examples of such diseases of the central nervous system in which excitotoxicity plays a role are stroke, hypoglycemia, hypoxia, trauma and epilepsy as acute disorders, but also chronic disorders in the sense of neurodegeneration such as Alzheimer's disease, dementia in AIDS, and amyotrophs Lateral sclerosis, Parkinson's disease, chronic alcoholism and others.
  • the GABA derivative gabapentin is also said to inhibit glu synthesis in the millimolar concentration range (Goldlust A, Su TZ, Welty DF, Taylor CP, Oxender DL, 1995, Effects of anticonvulsant drug gabapentin on the enzymes in metabolic pathways of glutamate and GABA. Epilepsy Res 22: 1-11); however, these concentrations cannot be achieved in vivo .
  • diseases of the central nervous system such as stroke, hypoglycemia, hypoxia , Trauma and epilepsy, Alzheimer's disease, dementia in AIDS, amyotrophic lateral sclerosis, Parkinson's disease and chronic alcoholism can be used.
  • These new drugs are said not to have the disadvantages of the drugs known in the art.
  • the medicaments can preferably influence the glutamatergic transmission and reduce the extracellular glutamate level and / or prevent the depolarization and overexcitation of postsynaptic cells, for example by presynaptically released glutamate.
  • a 2-pyrrolidinone derivative of the general formula is used to achieve this object in the R 1 and R 2 together with the carbon atom in the 4-position of the pyrrolidinone ring form a five to ten-membered saturated or unsaturated ring which, in addition to carbon atoms, can have up to 2 heteroatoms selected from oxygen, sulfur and nitrogen atoms and which is unsubstituted or with up to 3 substituents selected from hydroxyl groups, amino groups, C 1 -C 4 alkyl radicals, C 1 -C 4 alkoxy radicals and C 1 -C 4 alkylamino radicals are substituted, R 3 , R 4 , R 5 and R 6 each independently of one another are hydrogen atoms, halogen atoms, hydroxyl groups, amino groups, C 1 -C 10 alkyl radicals, C 1 -C 10 alkoxy radicals, C 1 -C 10 alkylamino radicals or C 6 -C 10 aryl radicals and R
  • alkyl radicals as well as the alkyl components of the alkoxy radicals and alkylamino radicals can be straight-chain or branched.
  • 2-pyrrolidinone derivatives which have a substituent in the 4-position as defined above have an excellent effect in reducing the extracellular glutamate level and therefore for the prophylaxis and treatment of diseases of the central nervous system such as stroke, hypoglycemia, Hypoxia, trauma and epilepsy, Alzheimer's disease, dementia in AIDS, amyotrophic lateral sclerosis, Parkinson's disease and chronic alcoholism can be used.
  • the compounds can also preferably prevent the depolarization and overexcitation of postsynaptic cells, for example by presynaptically released glutamate.
  • 2-pyrrolidinone derivatives according to the invention are largely uncritical insofar as the substitution in the 4-position of the pyrrolidinone ring is ensured.
  • 2-pyrrolidinone derivatives which are unsubstituted in the 3- and 5-positions or one or two alkyl substituents with up to 10 carbon atoms, preferably up to 6 carbon atoms and / or one or two aryl substituents with 6 to 10 carbon atoms, preferably phenyl groups, exhibit.
  • Substitution of the nitrogen atom of the 2-pyrrolidinone derivatives is also largely uncritical, but the nitrogen atom of the 2-pyrrolidinone derivatives according to the invention is preferably unsubstituted or substituted with a C 1 -C 6 alkyl radical or a C 1 -C 6 acyl radical.
  • the claimed 2-pyrrolidinone derivatives show optical isomerism. According to the invention, both the pure R and the pure S form of the pyrrolidinone derivatives are included, but also any racemic mixtures of the R and S form.
  • radicals R 1 and R 2 together with the carbon atom in the 4-position of the pyrrolidinone ring form a saturated or unsaturated five to ten-membered ring.
  • This ring can have up to two heteroatoms selected from oxygen, sulfur and nitrogen atoms and can be unsubstituted or with up to three substituents selected from hydroxyl groups, amino groups, C 1 -C 4 alkyl radicals, C 1 -C 4 alkoxy radicals and C 1 -C 4 alkylamino radicals.
  • radicals R 1 and R 2 preferably form an unsubstituted ring which preferably has no heteroatoms, is preferably saturated and particularly preferably consists of six carbon atoms, the carbon atom being included in the 4-position of the 2-pyrrolidinone ring.
  • a particularly preferred 2-pyrrolidinone derivative of the invention is 8-aza-spiro [5,4] decan-9-one (gabapentin lactam).
  • radicals R 3 , R 4 , R 5 and R 6 are different from hydrogen, structural isomers also occur in addition to the optical isomers (which are included according to the invention). All structural isomers and mixtures thereof are included in the 2-pyrrolidinone derivatives according to the invention.
  • 2-pyrrolidinone derivative instead of the 2-pyrrolidinone derivative as defined above, pharmacologically acceptable salts, in particular acid addition salts, of the 2-pyrrolidinone derivative can also be used.
  • the compounds according to the invention can be prepared in a manner known per se.
  • the 8-aza-spiro [5,4] decan-9-one which is particularly preferred according to the invention has already been described in the literature (Kearney AS, Mehta SC, Radebaugh GW, The effect of cyclodextrins on the rate of intramolecular lactamization of gabapentin in aqueous solution International Journal of Pharmaceutics, 78 (1992), 25-34 and the literature discussion already discussed above drug research 10, 1960, pages 243-250), however, the use of this compound as a therapeutic agent is not suggested.
  • the 8-aza-spiro [5,4] decan-9-one preferred according to the invention can be used as the lactam known compound gabapentin and can be prepared, for example, by irradiating a phosphate-buffered aqueous gabapentin solution with ultraviolet light. Lactamization of appropriately substituted gabapentin derivatives can be used to prepare substituted derivatives of 8-azaspiro [5,4] decan-9-one. Preferred are those derivatives which have a C 1 -C 4 alkyl radical, a halogen, a hydroxyl group or an amino group, preferably a C 1 -C 4 alkyl radical or a halogen atom.
  • connection can also be made according to the following scheme.
  • Monomethyl 1,1-cyclohexanediacetate is converted to the azide via the corresponding acid chloride.
  • the azide is broken down to the isocyanate by the Curtius process.
  • the isocyanate is then hydrolyzed to 1-methylamino-1-acetic acid cyclohexane methyl ester. Heating this substance in alkaline methanol under reflux for three days gives 8-aza-spiro [5,4] decan-9-one or gabapentin lactam.
  • a general synthesis instruction for the 4-substituted 2-pyrrolidinones according to the invention is based on the synthesis of 3-substituted GABA derivatives published by Andruszkiewicz and Silverman (R. Andruszkiewicz and RB Silverman, Synthesis 953-955 (1989)) of appropriately substituted ⁇ , ⁇ -unsaturated carboxylic acid esters (1), which are accessible, inter alia, by a Reformatzky reaction. After reaction with nitromethane, a Michael addition gives a nitro compound (2) which, after reduction with elemental hydrogen, is converted into the corresponding amino compound (3). After ester cleavage and the activation of the carboxylate function by a group which exits well (e.g. conversion into the carboxylic acid halide), the corresponding 4-substituted 2-pyrrolidinone is obtained with cyclization.
  • compositions according to the invention can be formulated in a manner known per se into medicaments for mammals, preferably humans.
  • the compositions according to the invention are present in a mixture with a pharmaceutical organic or inorganic carrier which is suitable for enteral or parenteral administrations.
  • compositions according to the invention When formulated as tablets, common pharmaceutical carriers such as sodium citrate, lactose, microcrystalline cellulose and starch, lubricants such as anhydrous silica, hydrogenated castor oil, magnesium stearate, sodium lauryl sulfate and talc, and binders such as starch paste, glucose, lactose, gum arabic, mannitol, magnesium trisilicate and talc used. If the compositions according to the invention are to be administered via liquids, customary liquid carriers can be used.
  • customary liquid carriers can be used.
  • a formulation for injections and infusions or as suppositories is also possible, as is known in the art and described in relevant standard works.
  • compositions according to the invention can also be formulated in a manner known per se as depot formulations or to medicaments with delayed or sustained release.
  • compositions according to the invention depends on the specific composition and other factors and can be determined by a person skilled in the art on the basis of the condition of the patient to be treated, the severity and type of the disease to be treated, possible side effects of the compounds, etc.
  • a solution of gabapentin (100 ⁇ M) in physiological buffer (composition below) with a pH of 7.4 was prepared and irradiated with ultraviolet light (260 and 330 nanometers) at 37 ° C for two hours.
  • the lactam 8-aza-spiro [5,4] decan-9-one is slowly formed. Due to the slow reaction rate, according to Kearney et al. (1992) assumed a yield of about 1%, which corresponds to a 1 ⁇ M solution.
  • This experiment clearly shows the increase in surviving retinal ganglion cells after pressure-related retinal ischemia from 17.4% ( ⁇ 4%) to 35.0% ( ⁇ 7%).
  • the neurodegeneration in this Glaucom model is based on an NMDA receptor-mediated Glu toxicity.
  • Gabapentin lactam was first tested in a model in which the release was caused by electrical stimulation.
  • the release speaks in this model both on tetrodotoxin and on extracellular Ca ++ ions.
  • the sections were subjected to a superfusion and electrically stimulated twice, using 540 pulses of 4 ms, 6 Hz and 60 mA.
  • the superfusion was carried out at room temperature, not at 37 ° C.
  • 100 ⁇ M of the Glu uptake blocker PDC was present, so that the re-uptake of released Glu is reduced.
  • TTX or gabapentin lactam was added 15 minutes before the second stimulation. It was found that the electrically induced release of Glu is partially inhibited by TTX, but not by gabapentin lactam. The quasi-physiological release of Glu is therefore not affected by gabapentin lactam.
  • the model of the endogenously formed [ 3 H] -Glu was also used to generate ischemic conditions in vitro .
  • oxygen and glucose were replaced by nitrogen and sucrose during the superfusion.
  • Sucrose was used instead of 11 mM glucose to maintain the osmolarity of the superfusion liquid. It is known that sucrose cannot be broken down into glucose and fructose in vitro .
  • the [ 3 H] -Glu release was at 37 ° during incubation and superfusion C performed.
  • gabapentin lactam significantly reduces neurotoxic [ 3 H] glu output in this in vitro ischemia model.
  • the compounds thereby prevent in vitro the large increase of extracellular tritium-Glu in (with the tritium-glutamine preloaded) hippocampal slices of the rat after replacement of O 2 by N 2 and of glucose by Succhrose clearly namely by approximately 50%.
  • the quasi-physiological action potential-mediated Glu release was not influenced by gabapentin lactam.
  • Example 1 was repeated with the modification that the gabapentin-containing solution was not irradiated with ultraviolet light, but was used directly in the experiment.
  • the comparison solution therefore contains only gabapentin, but not 8-aza-spiro [5,4] decan-9-one. In the corresponding experiments, no difference could be found between the samples treated with the gabapentin solution and the comparison samples.
  • Example 2 above was repeated, but the structurally similar compound gabapentin was used instead of 8-aza-spiro [5,4] decan-9-one. It was shown that gabapentin showed no protective effect against neurodegeneration in this Glaucom model.

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EP98963476A 1997-11-18 1998-11-17 An 4-stellung substituierte 2-pyrrolidinon-derivate zur verringerung des extrazellulären glutamat-spiegels Expired - Lifetime EP1032560B1 (de)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP04022320A EP1486487A1 (de) 1997-11-18 1998-11-17 An 4-Stellung substituierte 2-Pyrrolidinon-Derivate zur Verringerung des extrazellulären Glutamat-Spiegels
DK98963476T DK1032560T3 (da) 1997-11-18 1998-11-17 I 4-position substituerede 2-pyrrolidinon-derivater til reduktion af det ekstracellulære

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19751062 1997-11-18
DE19751062A DE19751062A1 (de) 1997-11-18 1997-11-18 An 4-Stellung substituierte 2-Pyrrolidinon-Derivate zur Verringerung des extrazellulären Glutamat-Spiegels
PCT/EP1998/007383 WO1999025683A1 (de) 1997-11-18 1998-11-17 An 4-stellung substituierte 2-pyrrolidinon-derivate zur verringerung des extrazellulären glutamat-spiegels

Related Child Applications (2)

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EP04022320A Division-Into EP1486487A1 (de) 1997-11-18 1998-11-17 An 4-Stellung substituierte 2-Pyrrolidinon-Derivate zur Verringerung des extrazellulären Glutamat-Spiegels
EP04022320A Division EP1486487A1 (de) 1997-11-18 1998-11-17 An 4-Stellung substituierte 2-Pyrrolidinon-Derivate zur Verringerung des extrazellulären Glutamat-Spiegels

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EP1032560B1 true EP1032560B1 (de) 2004-12-29

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EP04022320A Withdrawn EP1486487A1 (de) 1997-11-18 1998-11-17 An 4-Stellung substituierte 2-Pyrrolidinon-Derivate zur Verringerung des extrazellulären Glutamat-Spiegels

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US (1) US6384069B1 (da)
EP (2) EP1032560B1 (da)
JP (1) JP2001523659A (da)
AT (1) ATE285768T1 (da)
CA (1) CA2310319A1 (da)
CY (1) CY1105658T1 (da)
DE (2) DE19751062A1 (da)
DK (1) DK1032560T3 (da)
ES (1) ES2232976T3 (da)
PT (1) PT1032560E (da)
WO (1) WO1999025683A1 (da)

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US6781030B1 (en) 1998-11-02 2004-08-24 Trustee Of Tufts College, Ballou Hall Methods for cloning mammals using telophase oocytes
FR2796552A1 (fr) * 1999-07-21 2001-01-26 Centre Nat Rech Scient Nouvelle utilisation de derives de la beta-naphtoquinone et de leurs sels pour la fabrication de medicaments exercant un effet inhibiteur sur la liberation de glutamate dans le cerveau
ES2169690B1 (es) * 2000-10-06 2004-03-16 Diverdrugs Sl Trimeros de n-alquilglicina capaces de proteger a neuronas contra agresiones excitotoxicas, y composiciones que los contienen.
DE10210190A1 (de) * 2002-03-07 2003-09-25 Sanol Arznei Schwarz Gmbh Aza-Spiroverbindungen
DE10210195B4 (de) 2002-03-07 2005-12-15 Schwarz Pharma Ag Verwendung von 1,3-Diazaspiro-[4,5]decan-2,4-dithion zur Behandlung von Schmerz
EP1529528A1 (en) * 2003-11-07 2005-05-11 Universitätsklinikum Freiburg 2-pyrrolidone derivatives and their use in protecting mammalian cells against oxidation stress
AU2011298091B2 (en) 2010-08-31 2015-08-20 Accure Therapeutics, S.L. Agonists of neurotrophin receptors and their use as medicaments

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DE1445664A1 (de) * 1963-07-04 1969-11-27 Klinke Desitin Werk Verfahren zur Herstellung von alpha,alpha-disubstituierten Succinimiden
DD130243A1 (de) * 1977-03-23 1978-03-15 Wolfgang Kuehne Verfahren zur herstellung von alpha,alpha-disubstituierten bernsteinsaeureimiden
DE3631414A1 (de) * 1986-09-16 1988-03-24 Basf Ag Verfahren zur herstellung von (alpha)-pyrrolidonen, deren verwendung und neue (alpha)-pyrrolidone
DE3928183A1 (de) * 1989-08-25 1991-02-28 Goedecke Ag Lactamfreie cyclische aminosaeuren
US5319135A (en) 1989-08-25 1994-06-07 Warner-Lambert Company Process for cyclic amino acid anticonvulsant compounds
US5084479A (en) * 1990-01-02 1992-01-28 Warner-Lambert Company Novel methods for treating neurodegenerative diseases
DK0542795T5 (da) * 1990-08-03 1998-09-07 Smithkline Beecham Corp TNF-inhibitorer
AU2869092A (en) * 1991-10-11 1993-05-03 Smithkline Beecham Corporation Heterocyclic 3-phenylpyrrolidin-2-ones, their preparation and use for the manufacture of a medicament for inhibiting tumor necrosis factor production
US5929088A (en) * 1996-02-07 1999-07-27 Warner-Lambert Company Cyclic amino acids as pharmaceutical agents
US6020370A (en) * 1996-03-14 2000-02-01 Warner-Lambert Company Bridged cyclic amino acids as pharmaceutical agents
UA49011C2 (uk) 1996-03-14 2002-09-16 Варнер-Ламберт Компані Похідні циклічної амінокислоти, фармацевтична композиція та спосіб лікування

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CA2310319A1 (en) 1999-05-27
DE19751062A1 (de) 1999-07-08
WO1999025683A1 (de) 1999-05-27
US6384069B1 (en) 2002-05-07
DE59812460D1 (de) 2005-02-03
JP2001523659A (ja) 2001-11-27
PT1032560E (pt) 2005-04-29
EP1486487A1 (de) 2004-12-15
CY1105658T1 (el) 2010-12-22
ES2232976T3 (es) 2005-06-01
EP1032560A1 (de) 2000-09-06
DK1032560T3 (da) 2005-04-04
ATE285768T1 (de) 2005-01-15

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